The effects of dietary treatment with S-equol on learning and memory processes in middle-aged ovariectomized rats

Abstract

The use of over-the-counter botanical estrogens containing isolated soy isoflavones, including genistein and daidzein, has become a popular alternative to traditional hormone therapies. Menopausal women use these products as an aide in healthy aging, including for the maintenance of cognitive function. The safety and efficacy of many of these commercial preparations remains unknown. Previous research in our lab found that treatment of ovariectomized (OVX) female Long-Evans rats with genistein impaired working memory in an operant delayed spatial alternation (DSA) task and response learning in a plus-maze, but enhanced place learning assessed in the plus-maze. The present study further examined the effects of isolated isoflavones on working memory and place learning by treating middle-aged (12–13 month old) OVX female Long-Evans rats with S-equol, the exclusive enantiomer produced by metabolism of daidzein in the mammalian gut. S-equol binds selectively to ERβ with an affinity similar to that of genistein but has low transcriptional potency. For DSA testing, S-equol at 1.94, 0.97 mg, or 0 mg (sucrose control) was orally administered to animals daily, 30 minutes before behavioral testing, and again both 4 and 8 hours after the first treatment. Rats were tested on the DSA task following the first, morning dose. For place learning, rats received 0.97 mg S-equol every 4 hours during the light portion of the cycle beginning 48 hours prior to behavioral testing (total exposure 8.7 mg S-equol). S-equol treatment was largely without effect on the DSA and place learning tasks. This is the first study to test the behavioral effects of isolated S-equol in OVX rodents, and shows that, unlike genistein or estradiol, repeated daily treatment with this isoflavone metabolite does not alter learning and memory processes in middle-aged OVX rats.

Estrogens and cognition: Friends or foes?

“…Thus, the majority of studies described herein were conducted using virgin young adult female rats to test first how estrogens modulate learning and memory across memory systems before extending questions to contexts of aging, hormone timing, parity, and menopause etiology (Acosta et al., 2013; Daniel, 2012; Frick, 2009; Galea et al, 2014). It is important to note, however, estradiol-induced enhancements in place learning originally observed in young adults are also seen in middle aged (Neese et al, 2014) and elderly (Korol et al, 2007) multiparous rats, suggesting that our behavioral tasks and treatments are useful in assessing cognitive function across the lifespan.…”

“…Substantial progress has been made using a variety of experimental models to demonstrate that there is a window of opportunity around the perimenopausal period for estrogens to protect the brain against declines in cognitive function and related neurodegenerative diseases (Daniel, 2012; Gibbs, 2000; Resnick and Henderson, 2002). When administered to middle-aged female rodents close to the time of hormone deprivation, estrogens improve memory for several different cognitive tasks (Bimonte-Nelson et al, 2006; Daniel et al, 2006; Fernandez and Frick, 2004; Markham et al, 2002; Neese et al, 2014; Rodgers et al, 2010; Talboom et al, 2008). In contrast, estrogen-induced memory enhancements are not seen following prolonged periods of hormone deprivation (Daniel et al, 2006; Gibbs, 2000), a loss of responsiveness that extends to measures of neuronal plasticity and transmission (Daniel, 2012).…”

“…If so, the direction of estrogen effects on cognition will generalize to other tasks that sort according to the memory system predominating during the task, such as hippocampus or striatum. Delayed alternation in operant conditioning tasks is believed to rely on cortico-striatal processing and is impaired by estrogens including estradiol and genistein in young adult, middle-aged, and elderly rats (Neese et al, 2010a; 2010b; Neese et al, 2012; Wang et al, 2009; Neese et al 2014). For example, chronic treatments of estradiol initiated at the time of ovariectomy in 12-month-old female rats significantly impair working memory in a spatial alternation task (Figure 3) believed to rely on intact prefrontal cortex function.…”

“…Experiments were conducted using Fischer 344 x Brown Norway rats. d Pisani et al, 2012b; e Neese et al, 2014; f Zurkovsky et al, 2007; ES was infused directly into the dorsal hippocampus or dorsolateral striatum 48, 24, and 2 h before behavioral testing. g Korol et al, 2010; h Pisani et al, 2012a; i Pisani et al, 2013; j Tunur et al, 2012; k Korol et al, 2004; l Kent et al, 2005; m Zurkovsky et al, 2011; n Wang et al, 2008; o Wang et al, 2009; p Neese et al, 2010a; q Neese et al, 2012; r McElroy and Korol, 2005. …”

Improvement in Cognitive Function with Green Soybean Extract May Be Caused by Increased Neuritogenesis and BDNF Expression

“…Soybean is a rich source of proteins, oligosaccharides, dietary fibers, minerals and phytochemicals, particularly isoflavones [1,2]. Numerous beneficial effects of soybean and its components have been reported on cognitive function and oxidative damage [3][4][5][6][7]. Immature soybean seeds are usually green before it is harvested and becomes yellow during maturation.…”